U.S. patent number 7,618,965 [Application Number 11/227,697] was granted by the patent office on 2009-11-17 for (arylamidoanilino)nitroethylene compounds.
This patent grant is currently assigned to OSI Pharmaceuticals, Inc.. Invention is credited to Andrew Crew, An-Hu Li, Bijoy Panicker.
United States Patent |
7,618,965 |
Crew , et al. |
November 17, 2009 |
**Please see images for:
( Certificate of Correction ) ** |
(Arylamidoanilino)nitroethylene compounds
Abstract
Compounds represented by Formula (I): ##STR00001## or a
pharmaceutically acceptable salt or N-oxide thereof, wherein A, Q,
Y, R.sup.1, R.sup.2, and R.sup.5 are defined herein, are useful in
the treatment of tumors and cancers such as mastocytosis/mast cell
leukemia, gastrointestinal stromal tumors (GIST), germ cell tumors,
small cell lung carcinoma (SCLC), sinonasal natural killer/T-cell
lymphoma, testicular cancer (seminoma), thyroid carcinoma,
malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma,
acute myelogenous leukemia (AML), breast carcinoma, pediatric
T-cell acute lymphoblastic leukemia, neuroblastoma, mast cell
leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial
carcinoma, and prostate carcinoma.
Inventors: |
Crew; Andrew (Farmingdale,
NY), Li; An-Hu (Farmingdale, NY), Panicker; Bijoy
(Farmingdale, NY) |
Assignee: |
OSI Pharmaceuticals, Inc.
(Melville, NY)
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Family
ID: |
35819141 |
Appl.
No.: |
11/227,697 |
Filed: |
September 15, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20060069121 A1 |
Mar 30, 2006 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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60610676 |
Sep 17, 2004 |
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Current U.S.
Class: |
514/235.2;
546/166; 546/165; 544/128; 514/314; 514/311 |
Current CPC
Class: |
C07D
409/12 (20130101); A61P 35/00 (20180101); C07D
409/14 (20130101) |
Current International
Class: |
A61K
31/535 (20060101); A61K 31/47 (20060101); C07D
215/00 (20060101); C07D 215/02 (20060101); C07D
413/00 (20060101) |
Field of
Search: |
;546/165,166
;514/338,311,235.2,314 ;544/128 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 2004/063330 |
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Jul 2004 |
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WO |
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Primary Examiner: Andres; Janet L
Assistant Examiner: Robinson; Binta M
Parent Case Text
This application claims the benefit of U.S. Patent Application No.
60/610,676 filed 17 Sep. 2004.
Claims
What is claimed is:
1. A compound represented by Formula (I): ##STR00017## wherein: Q
is thienyl optionally substituted with 1-4 independent R.sup.3
substituents; Y is phenyl optionally substituted with 1-4
independent R.sup.4 substituents; A is quinolinyl optionally
substituted by 1-5 independent R.sup.41 substituents; R.sup.1 and
R.sup.2 are independently H, methyl, pyridyl, dimethylaminoethyl,
2-methoxyethyl, or 2-piperidinylethyl, each of which is optionally
substituted by 1-5 independent R.sup.42 substituents; or R.sup.1
and R.sup.2, taken together with the N atom to which they are
attached, form a piperidinyl or morpholinyl group, either
optionally substituted with 1-4 independent R.sup.42 substituents;
R.sup.3 is C.sub.0-6alkyl, cycloC.sub.3-10alkyl, haloalkyl,
halogen, cyanoC.sub.0-6alkyl, nitroC.sub.0-6alkyl,
hydroxyC.sub.0-6alkyl, C.sub.0-6alkylaminoC.sub.0-6alkyl,
acylC.sub.0-6alkyl, acyl, acylaminoC.sub.0-6alkyl, acylamino,
acyloxyC.sub.0-6alkyl, acyloxy, arC.sub.0-6alkyl,
heteroarylC.sub.0-6alkyl, arylhydrazino,
alkylsulfonamidoC.sub.0-6alkyl, arylsulfonamidoC.sub.0-6alkyl,
alkylsulfonylC.sub.0-6alkyl, arylsulfonylC.sub.0-6alkyl,
alkylsulfinylC.sub.0-6alkyl, heterocyclylsulfonylC.sub.0-6alkyl,
silyl, siloxyC.sub.0-6alkyl, alkenoxyC.sub.0-6alkyl,
alkynoxyC.sub.0-6alkyl, C.sub.1-6alkoxyC.sub.0-6alkyl,
C.sub.1-6alkylthioC.sub.0-6alkyl, C.sub.2-6alkenyl,
acylC.sub.2-6alkenyl, C.sub.2-6alkynyl, acylC.sub.2-6alkynyl,
arC.sub.0-6alkylaminoC.sub.0-6alkyl,
arC.sub.0-6alkylthioC.sub.0-6alkyl,
arC.sub.0-6alkoxyC.sub.0-6alkyl, arC.sub.0-6alkoxy,
arC.sub.0-6alkylthio, or arC.sub.0-6alkoxy; R.sup.4, R.sup.41, and
R.sup.42 each independently is and each is C.sub.0-6alkyl,
cycloC.sub.3-10alkyl, oxo, halogen, haloalkyl, cyanoC.sub.0-6alkyl,
nitroC.sub.0-6alkyl, hydroxyC.sub.0-6alkyl,
(C.sub.0-6alkyl)(C.sub.0-6alkyl)aminoC.sub.0-6alkyl,
(C.sub.0-6alkyl)(C.sub.0-6alkyl)amino(C.sub.1-6alkyl)(C.sub.0-6alkyl)amin-
o, acylaminoC.sub.0-6alkylamino, acylC.sub.0-6alkyl, acyl,
guanidinoC.sub.0-6alkyl, hydroxyiminoC.sub.0-6alkyl,
acylaminoC.sub.0-6alkyl, acylamino, acyloxyC.sub.0-6alkyl, acyloxy,
arC.sub.0-6alkyl, arC.sub.0-6alkyl, heteroarylC.sub.0-6alkyl,
heteroarylC.sub.0-6alkyl, heterocyclylC.sub.0-6alkyl,
cyanoaminoC.sub.0-6alkyl, C.sub.0-6alkylhydrazino,
heterocyclylamino, arC.sub.0-6alkylhydrazino,
alkylsulfonylC.sub.0-6alkyl,
arC.sub.0-6alkylsulfonylC.sub.0-6alkyl,
alkylsulfinylC.sub.0-6alkyl, alkylsulfonamidoC.sub.0-6alkyl,
arC.sub.0-6alkylsulfonamidoC.sub.0-6alkyl,
aminoC.sub.0-6alkylsulfonyl, C.sub.0-6alkylaminosulfonyl,
acylC.sub.1-6alkylsulfonyl, heterocyclylsulfonyl,
aminoC.sub.0-6alkylsulfinyl, acylC.sub.1-6alkylsulfinyl, silyl,
siloxy, alkenoxy, alkynoxy, C.sub.2-6alkenyl, acylC.sub.2-6alkenyl,
C.sub.2-6alkynyl, acylC.sub.2-6alkynyl, hydroxyC.sub.2-6alkynyl,
aminoC.sub.2-6alkynyl, C.sub.1-6alkoxyC.sub.0-6alkyl,
C.sub.1-6alkylthioC.sub.0-6alkyl,
hydroxyC.sub.1-6alkoxyC.sub.0-6alkyl,
hydroxyC.sub.1-6alkylthioC.sub.0-6alkyl,
acylC.sub.1-6alkoxyC.sub.0-6alkyl,
acylC.sub.1-6alkylthioC.sub.0-6alkyl,
C.sub.0-6alkylaminoC.sub.1-6alkoxyC.sub.0-6alkyl,
C.sub.0-6alkylaminoC.sub.1-6alkylthioC.sub.0-6alkyl,
acylaminoC.sub.1-6alkoxyC.sub.0-6alkyl,
acylaminoC.sub.1-6alkylthioC.sub.0-6alkyl,
arC.sub.0-6alkylaminoC.sub.0-6alkyl,
arC.sub.0-6alkylthioC.sub.0-6alkyl,
arC.sub.0-6alkoxyC.sub.0-6alkyl, arC.sub.0-6alkylamino,
arC.sub.0-6alkylaminoC.sub.0-6alkyl, arC.sub.0-6alkylthio,
arC.sub.0-6alkoxy, arC.sub.0-6alkylthio, or arC.sub.0-6alkoxy; and
R.sup.5 is H; or a pharmaceutically acceptable salt or N-oxide
thereof.
2. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt or N-oxide thereof, and a
pharmaceutically acceptable carrier.
3. A compound selected from:
N-(3-{[1-(dimethylamino)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmeth-
yl)amino]thiophene-2-carboxamide;
N-(4-{[1-[(2-morpholin-4-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-[(2-piperidin-1-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(3-{[1-[(2-methoxyethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin--
4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-[(pyridin-3-yl-methyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quin-
olin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-amino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]t-
hiophene-2-carboxamide;
N-(3-{[1-amino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]t-
hiophene-2-carboxamide;
N-(3-{[1-[(pyridin-3-yl-methyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quin-
olin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(3-{[1-[(2-(dimethylamino)ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-methylamino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)a-
mino]thiophene-2-carboxamide;
N-(4-{[1-[(2-methoxyethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin--
4-ylmethyl)amino]thiophene-2-carboxamide; or
N-(3-{[1-[(2-piperidin-1-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide; or a
pharmaceutically acceptable salt, or N-oxide, thereof.
4. A pharmaceutical composition comprising a compound of claim 3,
or a pharmaceutically acceptable salt or N-oxide thereof, and a
pharmaceutically acceptable carrier.
Description
BACKGROUND OF THE INVENTION
The present invention is directed to
(arylamidoanilino)nitroethylene compounds that are inhibitors of
c-Kit proto-oncogene (also known as Kit, CD-117, stem cell factor
receptor, mast cell growth factor receptor).
The c-Kit proto-oncogene is believed to be important in
embryogenesis, melanogenesis, hematopoiesis, and the pathogenesis
of mastocytosis, gastrointestinal tumors, and other solid tumors,
as well as certain leukemias, including AML. Accordingly, it would
be desirable to develop novel compounds that are inhibitors of the
c-Kit receptor.
Many of the current treatment regimes for hyperproliferative
disorders (cancer) utilize compounds that inhibit DNA synthesis.
Such compounds' mechanism of operation is to be toxic to cells,
particularly to rapidly dividing tumor cells. Thus, their broad
toxicity can be a problem to the subject patient. However, other
approaches to anti-cancer agents that act other than by the
inhibition of DNA synthesis have been explored to try to enhance
the selectivity of the anti-cancer action and thereby reduce
adverse side-effects.
It is known that a cell may become cancerous by virtue of the
transformation of a portion of its DNA into an oncogene (i.e. a
gene which, on activation, leads to the formation of malignant
tumor cells). Many oncogenes encode proteins that are aberrant
protein-tyrosine kinases capable of causing cell transformation. By
a different route, the overexpression of a normal proto-oncogenic
tyrosine kinase can also result in proliferative disorders,
sometimes resulting in a malignant phenotype. Alternatively,
co-expression of a receptor tyrosine kinase and its cognate ligand
within the same cell type may also lead to malignant
transformation.
Receptor tyrosine kinases are large enzymes which span the cell
membrane and possess i) an extracellular binding domain for growth
factors such as KIT ligand (also known as stem cell factor (SCF),
Steel factor (SLF) or mast cell growth factor (MGF)), ii) a
transmembrane domain, and iii) an intracellular portion which
functions as a kinase to phosphorylate specific tyrosine residues
in proteins. Binding of KIT ligand to KIT tyrosine kinase results
in receptor homodimerization, the activation of KIT tyrosine kinase
activity, and the subsequent phosphorylation of a variety of
protein substrates, many of which are effectors of intracellular
signal transduction, These events can lead to enhanced cell
proliferation or promote enhanced cell survival. With some receptor
kinases, receptor heterodimerization can also occur.
It is known that such kinases are frequently aberrantly expressed
in common human cancers such as breast cancer, head and neck
cancers, gastrointestinal cancer such as colon, rectal or stomach
cancer, leukemia, and ovarian, bronchial, lung or pancreatic
cancer. Kit kinase expression has been documented in a wide variety
of human malignancies such as mastocytosis/mast cell leukemia,
gastrointestinal stromal tumors (GIST), small cell lung carcinoma
(SCLC), sinonasal natural killer/T-cell lymphoma, testicular cancer
(seminoma), thyroid carcinoma, malignant melanoma, ovarian
carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia
(AML), breast carcinoma, pediatric T-cell acute lymphoblastic
leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial
carcinoma, and prostate carcinoma. The kinase activity of KIT has
been implicated in the pathophysiology of several of these--and
additional tumors--including breast carcinoma, SCLC, GIST, germ
cell tumors, mast cell leukemia, neuroblastoma, AML, melanoma and
ovarian carcinoma.
Several mechanisms of KIT activation in tumor cells have been
reported, including activating mutations, autocrine and paracrine
activation of the receptor kinase by its ligand, loss of
protein-tyrosine phosphatase activity, and cross activation by
other kinases. The transforming mechanisms initiated by the
activating mutations are thought to include dimer formation and
increased intrinsic activity of the kinase domain, both of which
result in constitutive ligand-independent kinase activation, and
possibly altered substrate specificity. More than thirty activating
mutations of the Kit protein have been associated with highly
malignant tumors in humans.
Accordingly, it has been recognized that inhibitors of receptor
tyrosine kinases are useful as selective inhibitors of the growth
of mammalian cancer cells. For example, Gleevec.TM. (also known as
imatinib mesylate, or ST1571), a 2-phenylpyrimidine tyrosine kinase
inhibitor that inhibits the kinase activity of the BCR-ABL fusion
gene product, was recently approved by the U.S. Food and Drug
Administration for the treatment of CML. Gleevec.TM., in addition
to inhibiting BCR-ABL kinase, also inhibits the KIT kinase and PDGF
receptor kinase, although it is not effective against all mutant
isoforms of the KIT kinase. Kit ligand-stimulated growth of MO7e
human leukemia cells is inhibited by Gleevec.TM., which also
induces apoptosis under these conditions. By contrast, GM-CSF
stimulated growth of MO7e human leukemia cells is not affected by
Gleevec.TM.. Further, in recent clinical studies using Gleevec.TM.
to treat patients with GIST, a disease in which KIT kinase is
involved in transformation of the cells, many of the patients
showed marked improvement.
These studies demonstrate how KIT kinase inhibitors can treat
tumors whose growth is dependent on KIT kinase activity. Other
kinase inhibitors show even greater kinase selectivity. For
example, the 4-anilinoquinazoline compound Tarceva.TM. inhibits
only EGF receptor kinase with high potency, although it can inhibit
the signal transduction of other receptor kinases, probably by
virtue of the fact that these receptors heterodimerize with EGF
receptor.
Although anti-cancer compounds such as those described above make a
significant contribution to the art, there is a continuing need for
improved anti-cancer pharmaceuticals, and it would be desirable to
develop new compounds with better selectivity or potency, or with
reduced toxicity or side effects.
SUMMARY OF THE INVENTION
Compounds represented by Formula (I):
##STR00002##
or a pharmaceutically acceptable salt or N-oxide thereof, are
useful in the treatment of tumors and cancers such as
mastocytosis/mast cell leukemia, gastrointestinal stromal tumors
(GIST), germ cell tumors, small cell lung carcinoma (SCLC),
sinonasal natural killer/T-cell lymphoma, testicular cancer
(seminoma), thyroid carcinoma, malignant melanoma, ovarian
carcinoma, adenoid cystic carcinoma, acute myelogenous leukemia
(AML), breast carcinoma, pediatric T-cell acute lymphoblastic
leukemia, neuroblastoma, mast cell leukemia, angiosarcoma,
anaplastic large cell lymphoma, endometrial carcinoma, and prostate
carcinoma.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a compound represented by
Formula (I):
##STR00003##
or a pharmaceutically acceptable salt or N-oxide thereof,
wherein:
Q is aryl or heteroaryl, either of which is optionally substituted
with 1-4 independent R.sup.3 substituents;
Y is aryl or heteroaryl, either of which is optionally substituted
with 1-4 independent R.sup.4 substituents;
A is aryl, heteroaryl, cycloC.sub.3-10alkyl, heterocyclyl,
cycloC.sub.3-10alkenyl, or heterocycloalkenyl, each of which is
optionally substituted by 1-5 independent R.sup.41
substituents;
R.sup.1 and R.sup.2 are C.sub.0-6alkyl, aryl, heteroaryl,
cycloC.sub.3-10alkyl, heterocyclyl, cycloC.sub.3-10alkenyl,
heterocycloalkenyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, each of
which is optionally substituted by 1-5 independent R.sup.42
substituents;
or R.sup.1 and R.sup.2, taken together with the N atom to which
they are attached, form a heterocyclyl, heterocycloalkenyl, or
heteroaryl, each of which is optionally substituted with 1-4
independent R.sup.42 substituents;
R.sup.3 is C.sub.0-6alkyl, cycloC.sub.3-10alkyl, haloalkyl,
halogen, cyanoC.sub.0-6alkyl, nitroC.sub.0-6alkyl,
hydroxyC.sub.0-6alkyl, C.sub.0-6alkylaminoC.sub.0-6alkyl,
acylC.sub.0-6alkyl, substituted acyl, acylaminoC.sub.0-6alkyl,
substituted acylamino, acyloxyC.sub.0-6alkyl, substituted acyloxy,
arC.sub.0-6alkyl, heteroarylC.sub.0-6alkyl, arylhydrazino,
alkylsulfonamidoC.sub.0-6alkyl, arylsulfonamidoC.sub.0-6alkyl,
alkylsulfonylC.sub.0-6alkyl, arylsulfonylC.sub.0-6alkyl,
alkylsulfinylC.sub.0-6alkyl, heterocyclylsulfonylC.sub.0-6alkyl,
silyl, siloxyC.sub.0-6alkyl, alkenoxyC.sub.0-6alkyl,
alkynoxyC.sub.0-6alkyl, C.sub.1-6alkoxyC.sub.0-6alkyl,
C.sub.1-6alkylthioC.sub.0-6alkyl, C.sub.2-6alkenyl,
acylC.sub.2-6alkenyl, C.sub.2-6alkynyl, acylC.sub.2-6alkynyl,
arC.sub.0-6alkylaminoC.sub.0-6alkyl,
arC.sub.0-6alkylthioC.sub.0-6alkyl,
arC.sub.0-6alkoxyC.sub.0-6alkyl, substituted arC.sub.0-6alkoxy,
substituted arC.sub.0-6alkylthio, or substituted
arC.sub.0-6alkoxy;
R.sup.4, R.sup.41, and R.sup.42 each independently is
C.sub.0-6alkyl, cycloC.sub.3-10alkyl, oxo, halogen, haloalkyl,
cyanoC.sub.0-6alkyl, nitroC.sub.0-6alkyl, hydroxyC.sub.0-6alkyl,
(C.sub.0-6alkyl)(C.sub.0-6alkyl)aminoC.sub.0-6alkyl,
(C.sub.0-6alkyl)(C.sub.0-6alkyl)amino(C.sub.1-6alkyl)(C.sub.0-6alkyl)amin-
o, acylaminoC.sub.0-6alkylamino, acylC.sub.0-6alkyl, substituted
acyl, guanidinoC.sub.0-6alkyl, hydroxyiminoC.sub.0-6alkyl,
acylaminoC.sub.0-6alkyl, substituted acylamino,
acyloxyC.sub.0-6alkyl, substituted acyloxy, arC.sub.0-6alkyl,
substituted arC.sub.0-6alkyl, heteroarylC.sub.0-6alkyl, substituted
heteroarylC.sub.0-6alkyl, heterocyclylC.sub.0-6alkyl,
cyanoaminoC.sub.0-6alkyl, C.sub.0-6alkylhydrazino,
heterocyclylamino, arC.sub.0-6alkylhydrazino,
alkylsulfonylC.sub.0-6alkyl,
arC.sub.0-6alkylsulfonylC.sub.0-6alkyl,
alkylsulfinylC.sub.0-6alkyl, alkylsulfonamidoC.sub.0-6alkyl,
arC.sub.0-6alkylsulfonamidoC.sub.0-6alkyl,
aminoC.sub.0-6alkylsulfonyl, C.sub.0-6alkylaminosulfonyl,
acylC.sub.1-6alkylsulfonyl, heterocyclylsulfonyl,
aminoC.sub.0-6alkylsulfinyl, acylC.sub.1-6alkylsulfinyl, silyl,
siloxy, alkenoxy, alkynoxy, C.sub.2-6alkenyl, acylC.sub.2-6alkenyl,
C.sub.2-6alkynyl, acylC.sub.2-6alkynyl, hydroxyC.sub.2-6alkynyl,
aminoC.sub.2-6alkynyl, C.sub.1-6alkoxyC.sub.0-6alkyl,
C.sub.1-6alkylthioC.sub.0-6alkyl,
hydroxyC.sub.1-6alkoxyC.sub.0-6alkyl,
hydroxyC.sub.1-6alkylthioC.sub.0-6alkyl,
acylC.sub.1-6alkoxyC.sub.0-6alkyl,
acylC.sub.1-6alkylthioC.sub.0-6alkyl,
C.sub.0-6-alkylaminoC.sub.1-6alkoxyC.sub.0-6alkyl,
C.sub.0-6alkylaminoC.sub.1-6alkylthioC.sub.0-6alkyl,
acylaminoC.sub.1-6alkoxyC.sub.0-6alkyl,
acylaminoC.sub.1-6alkylthioC.sub.0-6alkyl,
arC.sub.0-6alkylaminoC.sub.0-6alkyl,
arC.sub.0-6alkylthioC.sub.0-6alkyl,
arC.sub.0-6alkoxyC.sub.0-6alkyl, arC.sub.0-6alkylamino,
arC.sub.0-6alkylaminoC.sub.0-6alkyl, arC.sub.0-6alkylthio,
substituted arC.sub.0-6alkoxy, substituted arC.sub.0-6alkylthio, or
substituted arC.sub.0-6alkoxy; and
R.sup.5 is C.sub.0-6alkyl, C.sub.1-6alkoxyC.sub.1-6alkyl,
C.sub.1-6alkylthioC.sub.1-6alkyl,
C.sub.0-6alkylaminoC.sub.1-6alkyl, arC.sub.0-6alkyl, or a bridge
between the N atom to which it is attached and one of the C ring
atoms of Y, forming a bicyclic heteroaryl group.
In one aspect, the present invention is directed to a compound
represented by Formula (I), or a pharmaceutically acceptable salt
or N-oxide thereof, wherein Y is aryl optionally substituted with
1-4 independent R.sup.4 substituents; and the other variables are
as described above for Formula (I).
In an embodiment of this one aspect, the present invention is
directed to a compound represented by Formula (I), or a
pharmaceutically acceptable salt or N-oxide thereof, wherein Y is
aryl optionally substituted with 1-4 independent R.sup.4
substituents; Q is heteroaryl optionally substituted with 1-4
independent R.sup.3 substituents; and the other variables are as
described above for Formula (I).
In an embodiment of this one aspect, the present invention is
directed to a compound represented by Formula (I), or a
pharmaceutically acceptable salt or N-oxide thereof, wherein Y is
aryl optionally substituted with 1-4 independent R.sup.4
substituents; Q is thienyl optionally substituted with 1-4
independent R.sup.3 substituents; and the other variables are as
described above for Formula (I).
In a second aspect, the present invention is directed to a compound
represented by Formula (I), or a pharmaceutically acceptable salt
or N-oxide thereof, wherein Q is thienyl optionally substituted
with 1-4 independent R.sup.3 substituents; and the other variables
are as described above for Formula (I).
In an embodiment of this second aspect, the present invention is
directed to a compound represented by Formula (I), or a
pharmaceutically acceptable salt or N-oxide thereof, wherein Q is
thienyl optionally substituted with 1-4 independent R.sup.3
substituents; A is heteroaryl optionally substituted by 1-5
independent R.sup.41 substituents; and the other variables are as
described above for Formula (I).
The present invention includes the following compounds:
N-(3-{[1-(dimethylamino)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmeth-
yl)amino]thiophene-2-carboxamide;
N-(4-{[1-[(2-morpholin-4-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-[(2-piperidin-1-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(3-{[1-[(2-methoxyethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin--
4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-[(pyridin-3-yl-methyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quin-
olin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-amino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]t-
hiophene-2-carboxamide;
N-(3-{[1-amino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]t-
hiophene-2-carboxamide;
N-(3-{[1-[(pyridin-3-yl-methyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quin-
olin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(3-{[1-[(2-(dimethylamino)ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide;
N-(4-{[1-methylamino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)a-
mino]thiophene-2-carboxamide;
N-(4-{[1-[(2-methoxyethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin--
4-ylmethyl)amino]thiophene-2-carboxamide;
N-(3-{[1-[(2-piperidin-1-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(q-
uinolin-4-ylmethyl)amino]thiophene-2-carboxamide; or
a pharmaceutically acceptable salt, or N-oxide, thereof.
The present invention is also directed to a method of treating
hyperproliferative disorders, including breast cancer, head cancer,
or neck cancer, gastrointestinal cancer, leukemia, ovarian,
bronchial, lung, or pancreatic cancer, mastocytosis/mast cell
leukemia, gastrointestinal stromal tumors (GIST), germ cell tumors,
small cell lung carcinoma (SCLC), sinonasal natural killer/T-cell
lymphoma, testicular cancer (seminoma), thyroid carcinoma,
malignant melanoma, ovarian carcinoma, adenoid cystic carcinoma,
acute myelogenous leukemia (AML), breast carcinoma, pediatric
T-cell acute lymphoblastic leukemia, neuroblastoma, mast cell
leukemia, angiosarcoma, anaplastic large cell lymphoma, endometrial
carcinoma, and prostate carcinoma, by administering an effective
amount of a compound represented by Formula (I), or a
pharmaceutically acceptable salt thereof.
In the present invention, the nitro group pendent to the ethylene
group shown in Formula (I) can be in the cis or trans
configuration. The present invention includes both the cis and
trans isomers.
As used herein, "C.sub.0-6alkyl" is used to mean an alkyl having
0-6 carbons--that is, 0, 1, 2, 3, 4, 5, or 6 carbons in a straight
or branched configuration. An alkyl having no carbon is hydrogen
when the alkyl is a terminal group. An alkyl having no carbon is a
direct bond when the alkyl is a bridging (connecting) group.
As used herein unless otherwise specified, "alkyl", "alkenyl", and
"alkynyl" includes straight or branched configurations. Lower
alkyls, alkenyls, and alkynyls have 1-6 carbons. Higher alkyls,
alkenyls, and alkynyls have more than 6 carbons.
As used herein unless otherwise specified, "halogen" is fluorine,
chlorine, bromine or iodine.
As used herein unless otherwise specified, "substituted" is used to
mean having 1-5 independent C.sub.0-6alkyl, halogen, nitro, cyano,
haloalkyl, C.sub.0-6alkoxy, C.sub.0-6alkylthio, or
C.sub.0-6alkylamino substituents
As used herein unless otherwise specified, "haloalkyl" includes
alkyl groups substituted with one or more halogens, for example,
chloromethyl, 2-bromoethyl, 3-iodopropyl, trifluoromethyl,
perfluoropropyl, 8-chlorononyl, and the like.
As used herein unless otherwise specified, the terms "aryl" and
"ar" are well known to chemists and include, for example, phenyl
and naphthyl, as well as phenyl with one or more short alkyl groups
(tolyl, xylyl, mesityl, cumenyl, di(t-butyl)phenyl). Phenyl,
naphthyl, tolyl, and xylyl are preferred. "Substituted aryl" is an
aryl substituted with suitable substituents such as, for example,
acyl, substituted acyl, N-protected piperazinylsulfonyl,
piperazinylsulfonyl, N--C.sub.1-6alkylpiperazinyl sulfonyl,
hydroxyC.sub.1-6alkyl, heterocyclyl, halogen, nitro, amino,
C.sub.1-6alkylamino, cyano, or C.sub.1-6alkoxy.
As used herein unless otherwise specified, the term "cycloalkyl" is
well known to chemists and includes cyclic aliphatic ring
structures, optionally substituted with alkyl, hydroxyl, oxo, and
halo, such as cyclopropyl, methylcyclopropyl, cyclobutyl,
cyclopentyl, 2-hydroxycyclopentyl, cyclopentanonyl, cyclohexyl,
4-chlorocyclohexyl, cycloheptyl, cyclooctyl, and the like.
As used herein unless otherwise specified, the term "cycloalkyl" is
well known to chemists and includes cyclic aliphatic ring
structures having at least one ethylenic bond, optionally
substituted with alkyl, hydroxyl, oxo, and halo, for example,
methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl,
cyclohexenonyl, cyclohexenyl, 1,4-cyclohexadienyl, and the
like.
As used herein unless otherwise specified, "heterocyclyl" is well
known to chemists and includes unsaturated, mono or polycyclic
heterocyclic groups containing at least one N, S or O hetero-ring
atom such as, for example, tetrahydrofuranyl, tetrahydrofuryl,
pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiolanyl,
morpholinyl, piperazinyl, homopiperazinyl, dioxolanyl, dioxanyl,
indolinyl, or chromanyl and the like. Such heterocyclyls can be
suitably substituted with lower alkyl or oxo substituents.
As used herein unless otherwise specified, "heteroaryl" is well
known to chemists and includes partially saturated, mono or
polycyclic heterocyclic groups containing at least one N, S or O
hetero-ring atom such as, for example, pyrazolyl, pyridyl,
pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl,
pyrrolidinyl, indolyl, indolinyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl,
benzotriazolyl, tetrazolo-pyridazinyl, pyranyl, furyl, thienyl,
oxazolyl, isoxazolyl, oxazolyl, benzofuranyl, benzoxazolyl,
benzoxadiazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
benzothiazolyl, benzothiadiazolyl, benzofuranyl, or benzodioxyl,
imidazolyl, pyrrolyl, oxadiazolyl, quinolyl, benzotriazolyl, or
benzothienyl and the like. Such heterocyclyls can be suitably
substituted with lower alkyl or oxo substituents.
As used herein unless otherwise specified, "heterocycloalkenyl"
includes mono or polycyclic heterocyclic groups having at least one
ethylenic bond and containing at least one N, S or O hetero-ring
atom such as, for example, dihydropyranyl, dihydrofuran, pyrrolinyl
or the like. Such heterocycloalkenyls can be suitably substituted
with lower alkyl or oxo substituents.
As used herein unless otherwise specified, "acyl" includes for
example, carboxy, esterified carboxy, carbamoyl, lower
alkylcarbamoyl, lower alkanoyl, aroyl, heterocyclylcarbonyl, and
the like. Esterified carboxy includes substituted or unsubstituted
lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl,
hexyloxycarbonyl, 2-iodoethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, dimethylaminopropoxycarbonyl,
dimethylaminoethoxycarbonyl; substituted or unsubstituted
aryloxycarbonyl such as phenoxycarbonyl, 4-nitrophenoxycarbonyl,
2-naphthyloxycarbonyl; substituted or unsubstituted
ar(lower)alkoxycarbonyl such as benzyloxycarbonyl,
phenethyloxycarbonyl, benzhydryloxycarbonyl,
4-nitrobenzyloxycarbonyl, 3-methoxy-4-nitrobenzyloxycarbonyl; and
N-containing heterocyclyloxycarbonyl such as
N-methylpiperidyloxycarbonyl and the like.
As used herein unless otherwise specified,
"C.sub.0-6alkylhydrazino" may be 2-mono or
2,2-di(C.sub.0-6alkyl)hydrazino such as 2-methylhydrazino,
2,2-dimethylhydrazino, 2-ethylhydrazino, hydrazine,
2,2-diethylhydrazino, or the like.
As used herein unless otherwise specified, alkylamino such as
"C.sub.1-6alkylamino" may be mono or dialkylamino such as
methylamino, dimethylamino, N-methylethylamino or the like.
Similarly, other amino groups such as acylamino are understood to
include a C.sub.0-6alkyl at the unspecified amino bond site (one
being to the acyl, the second forming a connection to the core
structure, and the third unspecified).
As used herein unless otherwise specified, "arC.sub.0-6alkylamino"
may be mono or disubstitutedamino such as anilino, benzylamino,
N-methylanilino, N-benzylmethylamino or the like.
As used herein unless otherwise specified, "silyl" includes alkyl
and aryl substituted silyl groups such as, for example,
triethylsilyl, t-butyldiphenylsilyl, or the like.
As used herein unless otherwise specified, "siloxy" includes alkyl
and aryl substituted silyloxy groups such as, for example,
triethylsilyloxy, t-butyldiphenylsilyloxy, or the like.
As used herein unless otherwise specified, "sulfonyloxy" includes
sulfonyloxy groups substituted with aryl, substituted aryl, or
alkyl such as, for example, benzenesulfonyl, tosyl, mesyl or the
like.
As used herein unless otherwise specified, "heterocyclylamino"
includes unsaturated, mono or polycyclic heterocyclic groups
containing at least one N-ring atom which is attached to an amino
group such as, for example, 1-aminopiperidine, 1-aminomorpholine,
1-amino-4-methylpiperazine or the like.
As used herein unless otherwise specified (for example, by a dash
marking the point of attachment), chemical group names comprised of
multiple chemical terms are used according to standard chemical
convention, wherein each term modifies the following term and
wherein the rightmost term forms a covalent bond with the structure
to which the substituent is attached. For example, aralkylamino
includes benzylamino and phenethylamino attached through the amino
nitrogen, but not toluidino or N-methylanilino groups.
Formula (I) is shown without a definitive stereochemistry at
certain positions. The present invention includes all stereoisomers
of Formula (I) and pharmaceutically acceptable salts thereof.
Further, mixtures of stereoisomers as well as isolated specific
stereoisomers are also included. During the course of the synthetic
procedures used to prepare such compounds, or in using racemization
or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers. In
the present invention, the nitro group pendent to the ethylene
group shown in Formula (I) can be in the cis or trans
configuration. The present invention includes both the cis and
trans isomers.
The invention also encompasses a pharmaceutical composition that is
comprised of a compound of Formula (I) in combination with a
pharmaceutically acceptable carrier.
Preferably, the composition is comprised of a pharmaceutically
acceptable carrier and a non-toxic therapeutically effective amount
of a compound of Formula (I) as described above (or a
pharmaceutically acceptable salt or N-oxide thereof).
Moreover, within this preferred embodiment, the invention
encompasses a pharmaceutical composition for the treatment of
disease by the inhibition of the c-Kit kinase, which may be a
wild-type or mutant form of the protein, comprising a
pharmaceutically acceptable carrier and a non-toxic therapeutically
effective amount of compound of Formula (I) as described above (or
a pharmaceutically acceptable salt or N-oxide thereof).
The compounds and compositions of the present invention are
effective for treating mammals such as, for example, humans.
The term "pharmaceutically acceptable salts" refers to salts
prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound of the present invention is acidic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic bases, including inorganic
bases and organic bases. Salts derived from such inorganic bases
include aluminum, ammonium, calcium, copper (ic and ous), ferric,
ferrous, lithium, magnesium, manganese (ic and ous), potassium,
sodium, zinc and the like salts. Particularly preferred are the
ammonium, calcium, magnesium, potassium and sodium salts. Salts
derived from pharmaceutically acceptable organic non-toxic bases
include salts of primary, secondary, and tertiary amines, as well
as cyclic amines and substituted amines such as naturally occurring
and synthesized substituted amines. Other pharmaceutically
acceptable organic non-toxic bases from which salts can be formed
include ion exchange resins such as, for example, arginine,
betaine, caffeine, choline, N',N'-dibenzylethylenediamine,
diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,
ethanolamine, ethylenediamine, N-ethylmorpholine,
N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine,
isopropylamine, lysine, methylglucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethylamine, trimethylamine, tripropylamine, tromethamine and the
like.
When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include, for example, acetic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,
fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,
lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric,
pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid and the like. Particularly preferred are
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
methanesulfonic, and tartaric acids.
The pharmaceutical compositions of the present invention or used by
the methods of the present invention comprise a compound
represented by Formula (I) (or a pharmaceutically acceptable salt
or N-oxide thereof) as an active ingredient, a pharmaceutically
acceptable carrier and optionally other therapeutic ingredients or
adjuvants. The compositions include compositions suitable for oral,
rectal, topical, and parenteral (including subcutaneous,
intramuscular, and intravenous) administration, although the most
suitable route in any given case will depend on the particular
host, and nature and severity of the conditions for which the
active ingredient is being administered. The pharmaceutical
compositions may be conveniently presented in unit dosage form and
prepared by any of the methods well known in the art of
pharmacy.
In practice, the compounds represented by Formula (I), or
pharmaceutically acceptable salts or N-oxides thereof, of this
invention can be combined as the active ingredient in intimate
admixture with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier may take a wide
variety of forms depending on the form of preparation desired for
administration. E.g., oral or parenteral (including intravenous).
Thus, the pharmaceutical compositions of the present invention can
be presented as discrete units suitable for oral administration
such as capsules, cachets or tablets each containing a
predetermined amount of the active ingredient. Further, the
compositions can be presented as a powder, as granules, as a
solution, as a suspension in an aqueous liquid, as a non-aqueous
liquid, as an oil-in-water emulsion, or as a water-in-oil liquid
emulsion. In addition to the common dosage forms set out above, the
compound represented by Formula (I), or a pharmaceutically
acceptable salt or N-oxide thereof, may also be administered by
controlled release means and/or delivery devices. The compositions
may be prepared by any of the methods of pharmacy. In general, such
methods include a step of bringing into association the active
ingredient with the carrier that constitutes one or more necessary
ingredients. In general, the compositions are prepared by uniformly
and intimately admixing the active ingredient with liquid carriers
or finely divided solid carriers or both. The product can then be
conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include
a pharmaceutically acceptable carrier and a compound or a
pharmaceutically acceptable salt or N-oxide of Formula (I). The
compounds of Formula (I), or pharmaceutically acceptable salts or
N-oxides thereof, can also be included in pharmaceutical
compositions in combination with one or more other therapeutically
active compounds.
The pharmaceutical compositions of this invention include a
pharmaceutically acceptable liposomal formulation containing a
compound of Formula (I) or a pharmaceutically acceptable salt or
N-oxide thereof.
The pharmaceutical carrier employed can be, for example, a solid,
liquid, or gas. Examples of solid carriers include lactose, terra
alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium
stearate, and stearic acid. Examples of liquid carriers are sugar
syrup, peanut oil, olive oil, and water. Examples of gaseous
carriers include carbon dioxide and nitrogen.
In preparing the compositions for oral dosage form, any convenient
pharmaceutical media may be employed. For example, water, glycols,
oils, alcohols, flavoring agents, preservatives, coloring agents,
and the like may be used to form oral liquid preparations such as
suspensions, elixirs and solutions; while carriers such as
starches, sugars, microcrystalline cellulose, diluents, granulating
agents, lubricants, binders, disintegrating agents, and the like
may be used to form oral solid preparations such as powders,
capsules and tablets. Because of their ease of administration,
tablets and capsules are the preferred oral dosage units whereby
solid pharmaceutical carriers are employed. Optionally, tablets may
be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be
prepared by compression or molding, optionally with one or more
accessory ingredients or adjuvants. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as powder or granules,
optionally mixed with a binder, lubricant, inert diluent, surface
active or dispersing agent or other such excipient. These
excipients may be, for example, inert diluents such as calcium
carbonate, sodium carbonate, lactose, calcium phosphate or sodium
phosphate; granulating and disintegrating agents, for example, corn
starch, or alginic acid; binding agents, for example, starch,
gelatin or acacia; and lubricating agents, for example, magnesium
stearate, stearic acid or talc. The tablets may be uncoated or they
may be coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer time. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate may
be used.
In hard gelatin capsules, the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin. In soft gelatin capsules, the active
ingredient is mixed with water or an oil medium, for example,
peanut oil, liquid paraffin or olive oil. Molded tablets may be
made by molding in a suitable machine, a mixture of the powdered
compound moistened with an inert liquid diluent. Each tablet
preferably contains from about 0.05 mg to about 5 g of the active
ingredient and each cachet or capsule preferably containing from
about 0.05 mg to about 5 g of the active ingredient.
For example, a formulation intended for the oral administration to
humans may contain from about 0.5 mg to about 5 g of active agent,
compounded with an appropriate and convenient amount of carrier
material, which may vary from about 5 to about 95 percent of the
total composition. Unit dosage forms will generally contain between
from about 1 mg to about 2 g of the active ingredient, typically 25
mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg,
or 1000 mg.
Pharmaceutical compositions of the present invention suitable for
parenteral administration may be prepared as solutions or
suspensions of the active compounds in water. A suitable surfactant
can be included such as, for example, hydroxypropylcellulose.
Dispersions can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof in oils. Further, a preservative can
be included to prevent the detrimental growth of
microorganisms.
Pharmaceutical compositions of the present invention suitable for
injectable use include sterile aqueous solutions or dispersions.
Furthermore, the compositions can be in the form of sterile powders
for the extemporaneous preparation of such sterile injectable
solutions or dispersions. In all cases, the final injectable form
must be sterile and must be effectively fluid for easy
syringability. The pharmaceutical compositions must be stable under
the conditions of manufacture and storage; thus, preferably should
be preserved against the contaminating action of microorganisms
such as bacteria and fungi. The carrier can be a solvent or
dispersion medium containing, for example, water, ethanol, polyol
(e.g., glycerol, propylene glycol and liquid polyethylene glycol),
vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a
form suitable for topical use such as, for example, an aerosol,
cream, ointment, lotion, dusting powder, or the like. Further, the
compositions can be in a form suitable for use in transdermal
devices. These formulations may be prepared, utilizing a compound
represented by Formula (I) of this invention, or a pharmaceutically
acceptable salt or N-oxide thereof, via conventional processing
methods. As an example, a cream or ointment is prepared by admixing
hydrophilic material and water, together with about 5 wt % to about
10 wt % of the compound, to produce a cream or ointment having a
desired consistency.
Pharmaceutical compositions of this invention can be in a form
suitable for rectal administration wherein the carrier is a solid.
It is preferable that the mixture forms unit dose suppositories.
Suitable carriers include cocoa butter and other materials commonly
used in the art. The suppositories may be conveniently formed by
first admixing the composition with the softened or melted
carrier(s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as
appropriate, one or more additional carrier ingredients such as
diluents, buffers, flavoring agents, binders, surface-active
agents, thickeners, lubricants, preservatives (including
anti-oxidants) and the like. Furthermore, other adjuvants can be
included to render the formulation isotonic with the blood of the
intended recipient. Compositions containing a compound described by
Formula (I), or pharmaceutically acceptable salts or N-oxides
thereof, may also be prepared in powder or liquid concentrate
form.
Generally, dosage levels on the order of from about 0.01 mg/kg to
about 150 mg/kg of body weight per day are useful in the treatment
of the above-indicated conditions, or alternatively about 0.5 mg to
about 10 g per patient per day. For example, breast cancer, head
and neck cancers, and gastrointestinal cancer such as colon, rectal
or stomach cancer may be effectively treated by the administration
of from about 0.01 to 100 mg of the compound per kilogram of body
weight per day, or alternatively about 0.5 mg to about 7 g per
patient per day.
Similarly, leukemia, ovarian, bronchial, lung, and pancreatic
cancer may be effectively treated by the administration of from
about 0.01 to 100 mg of the compound per kilogram of body weight
per day, or alternatively about 0.5 mg to about 7 g per patient per
day.
Mastocytosis/mast cell leukemia, gastrointestinal stromal tumors
(GIST), small cell lung carcinoma (SCLC), sinonasal natural
killer/T-cell lymphoma, testicular cancer (seminoma), thyroid
carcinoma, malignant melanoma, ovarian carcinoma, adenoid cystic
carcinoma, acute myelogenous leukemia (AML), breast carcinoma,
pediatric T-cell acute lymphoblastic leukemia, angiosarcoma,
anaplastic large cell lymphoma, endometrial carcinoma, and prostate
carcinoma may be effectively treated by the administration of from
about 0.01 to 100 mg of the compound per kilogram of body weight
per day, or alternatively about 0.5 mg to about 7 g per patient per
day.
It is understood, however, that the specific dose level for any
particular patient will depend upon a variety of factors including
the age, body weight, general health, sex, diet, time of
administration, route of administration, rate of excretion, drug
combination and the severity of the particular disease undergoing
therapy.
The compounds of the present invention, or pharmaceutically
acceptable salts or N-oxides thereof, can also be effectively
administered in conjunction with other cancer therapeutic
compounds. For example, cytotoxic agents and angiogenesis
inhibiting agents can be advantageous co-agents with the compounds
of the present invention. Accordingly, the present invention
includes compositions comprising the compounds represented by
Formula (I), or a pharmaceutically acceptable salt or N-oxide
thereof, and a cytotoxic agent or an angiogenesis-inhibiting agent.
The amounts of each can be therapeutically effective alone--in
which case the additive effects can overcome cancers resistant to
treatment by monotherapy. The amounts of any can also be
subtherapeutic--to minimize adverse effects, particularly in
sensitive patients.
It is understood that the treatment of cancer depends on the type
of cancer. For example, lung cancer is treated differently as a
first line therapy than are colon cancer or breast cancer treated.
Even within lung cancer, for example, first line therapy is
different from second line therapy, which in turn is different from
third line therapy. Newly diagnosed patients might be treated with
cisplatinum containing regimens. Were that to fail, they move onto
a second line therapy such as a taxane. Finally, if that failed,
they might get a tyrosine kinase EGFR inhibitor as a third line
therapy. Further, The regulatory approval process differs from
country to country. Accordingly, the accepted treatment regimens
can differ from country to country. Nevertheless, the compounds of
the present invention, or pharmaceutically acceptable salts or
N-oxides thereof, can be beneficially co-administered in
conjunction or combination with other such cancer therapeutic
compounds. Such other compounds include, for example, a variety of
cytotoxic agents (alkylators, DNA topoisomerase inhibitors,
antimetabolites, tubulin binders); inhibitors of angiogenesis; and
different other forms of therapies including kinase inhibitors such
as Tarceva, monoclonal antibodies, and cancer vaccines. Other such
compounds that can be beneficially co-administered with the
compounds of the present invention include doxorubicin,
vincristine, cisplatin, carboplatin, gemcitabine, and the taxanes.
Thus, the compositions of the present invention include a compound
according to Formula (I), or a pharmaceutically acceptable salt or
N-oxide thereof, and an anti-neoplastic, anti-tumor,
anti-angiogenic, or chemotherapeutic agent.
The compounds of the present invention, or pharmaceutically
acceptable salts or N-oxides thereof, can also be effectively
administered in conjunction with other therapeutic compounds, aside
from cancer therapy. For example, therapeutic agents effective to
ameliorate adverse side-effects can be advantageous co-agents with
the compounds of the present invention.
C-KIT H526 Cell Assay Protocol
I. Assay for Inhibition of c-Kit in Intact Cells
The ability of compounds to inhibit the tyrosine kinase activity of
c-Kit was determined in a cell-based ELISA assay using the H526
cell line (ATCC # CRL-5811), which was originally derived from a
human small cell lung cancer. The assay determines the ability of
compounds to block ligand-stimulated tyrosine phosphorylation of
the wild-type c-Kit receptor protein that is endogenously expressed
in H526 cells. Cells are pre-incubated with compounds at various
concentrations prior to addition of stem cell factor (SCF), the
ligand for the c-Kit receptor tyrosine kinase. Cell lysates are
then prepared and the c-Kit protein is captured onto a c-Kit
antibody-coated 96-well ELISA plate. The phosphotyrosine content of
the receptor protein is then monitored by quantitation of the
degree of binding of an antibody that recognizes only the
phosphorylated tyrosine residues within the captured protein. The
antibody used has a reporter enzyme (e.g. horseradish peroxidase,
HRP) covalently attached, such that binding of antibody to
phosphorylated c-Kit can be determined quantitatively by incubation
with an appropriate HRP substrate.
In the assays below, the following abbreviations are used: HRP for
horseradish peroxidase, BSA for bovine serum albumin, EDTA for
ethylenediaminetetraacetic acid, PBS for phosphate-buffered saline,
SCF for stem cell factor, DMSO for dimethylsulfoxide, rt for room
temperature, min for minute, and h for hour. The stock reagents
used are as follows:
Cell Lysis Buffer:
50 mM Tris-HCl, pH 7.4
150 mM NaCl
10% Glycerol
1% Triton X-100
0.5 mM EDTA
1 .mu.g/mL leupeptin
1 .mu.g/mL aprotinin
1 mM Sodium orthovanadate
Anti c-Kit Antibody:
0.5 .mu.g/mL anti c-Kit Ab-3 (Lab Vision, catalog #MS289P1) in 50
mM Sodium bicarbonate, pH 9.
ELISA Assay Plates:
ELISA assay plates are prepared by addition of 100 .mu.L of anti
c-Kit antibody to each well of a 96-well Microlite-2 plate (Dynex,
catalog #7417), followed by incubation at 37.degree. C. for 2 h.
The wells are then washed twice with 300 .mu.L wash buffer.
Plate Wash Buffer:
PBS containing 0.5% Tween-20 (PBST)
Cell Assay Medium:
RPMI with 0.1% BSA
pY20-HRP:
25 ng/mL pY20-HRP (Calbiochem, catalog #525320) in PBS, containing
0.5% Tween-20, 5% BSA, 1 mM Sodium orthovanadate
HRP Substrate:
Chemoluminescent detection reagent (Pierce, catalog #37075)
Assay Protocol
Cultures of H526 cells, growing in RPMI with 10% fetal calf serum,
were collected by centrifugation, washed twice with PBS, and
suspended in cell assay medium. Cells were then distributed into a
V-bottom 96-well plate at 7.5.times.10.sup.4 cells per well in 100
.mu.L cell assay medium.
Compound dilutions were prepared from 10 mM DMSO stocks by dilution
in cell assay medium, the final concentration of DMSO in the assay
being 0.1%. To compound incubation wells, 50 .mu.L of the test
compound was added (compounds are assayed at concentrations between
0.1 nM and 100 .mu.M); to positive and negative control wells, 50
.mu.L cell assay medium containing 0.1% DMSO was added. The cells
were then incubated with compound at 37.degree. C. for 3 h. SCF
(R&D Systems, catalog #255-SC-010) was then added in order to
stimulate the c-Kit receptor and induce its tyrosine
phosphorylation. Then, 10 .mu.L of a 1.6 .mu.g/mL solution of SCF
in cell assay medium was added to all wells apart from the negative
control wells, and the cells were incubated for an additional 15
min at 37.degree. C. Following the addition of ice-cold PBS, the
plate was centrifuged at 1000 rpm for 5 min, the medium removed by
aspiration, and the cell pellet lysed by the addition of 120 .mu.L
ice-cold cell lysis buffer per well. The plate was kept on ice for
20 min and 100 .mu.L of the cell lysates from each well were then
transferred to the wells of an ELISA assay plate and incubated at
4.degree. C. for 16 h.
Following incubation of the cell lysates in the ELISA plate, the
wells were washed 4 times with 300 .mu.L wash buffer, then 100
.mu.L of the phosphotyrosine detection antibody pY20-HRP was added
to each well and the plate incubated at rt for 2 h. The wells were
then washed 4 times with 300 .mu.L wash buffer. Then, 50 .mu.L of
the chemiluminescent HRP substrate was added to each well for
luminometric quantitation of the amount of antiphosphotyrosine-HRP
conjugate bound to the plate.
Comparison of the assay signals obtained in the presence of
compound with those of the positive and negative controls (cells
incubated in the presence or absence of SCF, with no compound
added), allows the degree of inhibition of c-Kit receptor tyrosine
phosphorylation to be determined over a range of compound
concentrations. These inhibition values were fitted to a sigmoidal
dose-response inhibition curve to determine the IC50 values (i.e.
the concentration of compound that inhibits SCF-induced tyrosine
phosphorylation of the c-Kit protein by 50%).
The compounds of this invention reduced the ability of Kit to
phosphorylate poly(Glu:Tyr) in the above assay, thus demonstrating
direct inhibition of the c-Kit receptor tyrosine kinase activity.
IC.sub.50 values in this assay were between 90 nM and 1.0
.mu.M.
EXPERIMENTAL
The EXAMPLES of the present invention were prepared according to
the following procedures:
Referring to the scheme shown below, reaction of aminothiophene 1
with aldehydes under reducing conditions affords secondary amines
such as compound 2--for example, in the presence of a mixture of
triethylsilane and trifluoroacetic acid, or other reagents such as
(but not limited to) sodium cyanoborohydride, sodium
triacetoxyborohydride, sodium borohydride and hydrogen.
Reaction of the resulting ester with a phenylenediamine under
Weinreb amidation conditions (for example, in the presence of alkyl
aluminum reagents such as (but not limited to) trimethylaluminum or
chlorodimethylaluminum in a neutral solvent such as toluene or
dichloromethane (Synthetic Communications, (1982), 12, 989))
followed by reaction with 1,1-bis(methylthio)-2-nitroethylene gives
amino(thio)nitroethylenes such as compound 4.
Heating these amino(thio)nitroethylenes in the presence of an amine
then yields diaminonitroethylenes such as EXAMPLE 3.
In the section below, the following abbreviations are used: Me for
methyl, Et for ethyl, Ph for phenyl, EtOAc for ethyl acetate, DMSO
for dimethylsulfoxide, DCM for dichloromethane, TFA for
trifluoroacetic acid, MS for mass spectroscopy, ES for
electrospray, rt for room temperature, min for minute, and h for
hour.
Example 1
N-(3-{[1-[(dimethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmet-
hyl)amino]thiophene-2-carboxamide
##STR00004##
EXAMPLE 1 was prepared by the following procedure:
##STR00005##
Part 1:
Methyl 3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate (2): A
mixture of 3-amino-thiophene-2-carboxylic acid methyl ester (5 g,
31.8 mmol) and 4-quinoline-carboxaldehyde (5.25 g, 33.4 mmol) in
TFA/CH.sub.2Cl.sub.2 (75 mL, 75 mL) was heated at 50.degree. C. for
3.5 h. The solution was cooled in an ice bath and triethylsilane
(10.2 mL, 63.6 mmol) was added drop-wise over 5 min. The reaction
mixture was stirred at 50.degree. C. for 3.5 h, cooled to rt, and
500 mL of CH.sub.2Cl.sub.2 was added. The reaction mixture was
basified with 10 N NaOH (pH 6-7) followed by sat. NaHCO.sub.3 (pH
8). The CH.sub.2Cl.sub.2 layer was separated and the aqueous layer
was extracted with CH.sub.2Cl.sub.2 (2.times.100 mL). The organic
extracts were combined, washed with brine, dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo to yield the
crude product, which was triturated with hexane to give pure methyl
3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate as white
solid. MS (ES): m/z 298.55 (100) [MH.sup.+]; .sup.1H-NMR (400
MHz/CDCl.sub.3): .delta. 3.87 (s, 3H), 5.00 (d, J=4.0 Hz, 2H), 6.48
(d, J=5.6 Hz, 1H), 7.30 (d, J=5.6 Hz, 1H), 7.36 (m, 1H), 7.41 (d,
J=4.4 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.76 (t, J=9.6 Hz, 1H), 8.01
(d, J=8.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.86 (d, J=4.4 Hz,
1H).
Part 2:
N-(3-Aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide
(3): To a solution of 1,3 phenylenediamine (5.43 g, 50.3 mmol) in
anhydrous toluene (100 mL) was added AlMe.sub.3 (2M in toluene, 7.5
mL, 15.1 mmol) and the solution was stirred at rt overnight. Methyl
3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxylate (3 g, 10.05
mmol) was added and the mixture was stirred at 130.degree. C. for 3
h. The reaction mixture was cooled to rt and the toluene was
decanted. To the remaining residue, 50 mL of 2N NaOH and 100 mL of
CH.sub.2Cl.sub.2 were added and the solution stirred for 30 min.
The CH.sub.2Cl.sub.2 layer was separated and the aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The toluene and
CH.sub.2Cl.sub.2 layers were combined, washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
Purification by silica gel chromatography (50% hexanes:ethyl
acetate.fwdarw.100% ethyl acetate) followed by trituration of the
solid with CH.sub.2Cl.sub.2 yielded pure
N-(3-aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide
as a tan powder. MS (ES): m/z 374.86 (100) [MH.sup.+]; .sup.1H NMR
(DMSO-d.sup.6, 400 MHz): .delta. 4.98-4.50 (m, 2H), 5.04 (d, J=5.6
Hz, 2H), 6.25 (d, J=7.2 Hz, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.79 (d,
J=5.6 Hz, 1H), 6.89 (t, J=8.0 Hz, 1H), 6.96-6.97 (m, 1H), 7.39 (d,
J=4.4 Hz, 1H), 7.55 (d, J=5.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.78
(t, J=6.8 Hz, 1H), 8.00-8.05 (m, 2H), 8.21 (d, J=8.0 Hz, 1H), 8.82
(d, J=4.4 Hz, 1H), 9.08 (s, 1H).
Part 3:
N-(3-{[1-(methylthio)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)-
amino]thiophene-2-carboxamide (4): To a solution of
1,1-bis(methylthio)-2-nitroethylene (1.4 g, 8.33 mmol) in MeOH (75
mL) was added
N-(3-Aminophenyl)-3-[(quinolin-4-ylmethyl)amino]thiophene-2-car-
boxamide (2.1 g, 8.33 mmol) and the mixture was stirred at
85.degree. C. overnight. The reaction mixture was cooled to rt and
the yellow precipitate formed was filtered, washed with MeOH, and
dried under vacuum to give
N-(3-{[1-(methylthio)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-y-
lmethyl)amino]thiophene-2-carboxamide as yellow solid. MS (ES): m/z
492.02 (100) [MH.sup.+]; .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
.delta. 2.47 (s, 2H), 3.17 (d, J=5.6 Hz, 1H), 5.10 (d, J=5.2 Hz,
2H), 6.78 (s, 1H), 6.81 (d, J=5.2 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H),
7.35-7.43 (m, 2H), 7.63 (d, J=5.2 Hz, 1H), 7.65-7.72 (m, 2H),
7.77-7.85 (m, 3H), 8.05-8.15 (m, 2H), 8.24 (dd, J=8.0, 7.2 Hz, 1H),
8.42 (d, J=4.0 Hz, 1H), 9.56 (s, 1H).
Part 4:
N-(3-{[1-[(dimethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylme-
thyl)amino]thiophene-2-carboxamide:
N-(3-{[1-(methylthio)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)-
amino]thiophene-2-carboxamide (75 mg, 0.153 mmol) and dimethylamine
(3 mL, 2N in MeOH) were stirred at 85.degree. C. overnight in a
sealed tube. The reaction was concentrated in vacuo and the
resultant crude product was purified using preparative HPLC
purification to give EXAMPLE 1 as a yellow powder. MS (ES): m/z
488.69 (100) [MH.sup.+]; .sup.1H NMR (DMSO-d.sub.6, 400 MHz):
.delta. 2.89 (s, 6H), 5.08 (d, J=6.0 Hz, 2H), 6.57 (s, 1H),
6.77-6.83 (m, 2H), 7.17 (t, J=8.4 Hz, 1H), 7.23-7.31 (m, 2H), 7.41
(d, J=3.6 Hz, 1H), 7.51 (t, J=2 Hz, 1H), 7.62 (d, J=5.6 Hz, 1H),
7.68 (dt, J=8.0, 1.2 Hz, 1H), 7.78-7.83 (m, 1H), 8.06 (d, J=7.6 Hz,
2H), 8.84 (d, J=4.8 Hz, 1H).
The following analogues were prepared using
N-(3-{[1-(methylthio)-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)-
amino]thiophene-2-carboxamide (EXAMPLE 1, part 3) and the
appropriate amine, according to the procedure described above for
EXAMPLE 1, part 4.
Example 2
N-(4-{[1-[(2-morpholin-4-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(qu-
inolin-4-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 573.97 [MH.sup.+]
##STR00006##
Example 3
N-(4-{[1-[(2-piperidin-1-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(qu-
inolin-4-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 571.58 [MH.sup.+]
##STR00007##
Example 4
N-(3-{[1-[(2-methoxyethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-
-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 519.07 (100) [MH.sup.+]
##STR00008##
Example 5
N-(4-{[1-[(pyridin-3-yl-methyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quino-
lin-4-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 552.06 [MH.sup.+]
##STR00009##
Example 6
N-(4-{[1-amino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]th-
iophene-2-carboxamide
MS (ES): 461.09 [MH.sup.+]
##STR00010##
Example 7
N-(3-{[1-amino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)amino]th-
iophene-2-carboxamide
MS (ES): 461.10 (100) [MH.sup.+]
##STR00011##
Example 8
N-(3-{[1-[(pyridin-3-yl-methyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quino-
lin-4-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 551.83 (100) [MH.sup.+]
##STR00012##
Example 9
N-(3-{[1-[(2-(dimethylamino)ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(qu-
inolin-4-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 532.17 (100) [MH.sup.+]
##STR00013##
Example 10
N-(4-{[1-methylamino-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-ylmethyl)am-
ino]thiophene-2-carboxamide
MS (ES): 475.05 [MH.sup.+]
##STR00014##
Example 11
N-(4-{[1-[(2-methoxyethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(quinolin-4-
-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 518.84 [MH.sup.+]
##STR00015##
Example 12
N-(3-{[1-[(2-piperidin-1-yl-ethyl)amino]-2-nitrovinyl]amino}phenyl)-3-[(qu-
inolin-4-ylmethyl)amino]thiophene-2-carboxamide
MS (ES): 572.16 (100) [MH.sup.+]
##STR00016##
* * * * *